Scientists have known for some time
that throwing off the body's circadian rhythm
can negatively affect body chemistry. In fact,
workers whose sleep-wake cycles are disrupted
by night shifts are more susceptible to chronic
inflammatory conditions such as diabetes, obesity
and cancer.

Salk researchers have now found a possible
molecular link between circadian rhythm disturbances
and an increased inflammatory response.
In a study published in Proceedings of the
National Academy of Sciences, the Salk team
found that the absence of a key circadian clock
component called cryptochrome (CRY) leads to
the activation of a signaling system that elevates
levels of inflammatory molecules in the body.

Cryptochrome serves as a brake to slow
the circadian clock's activity, signaling our
biological systems to wind down each evening.
In the morning, CRY stops inhibiting the clock's
activity, helping our physiology ramp up for the
coming day.

"There is compelling evidence that lowgrade,
constant inflammation could be the
underlying cause of chronic conditions such as
diabetes, obesity and cancer," says senior author
Inder Verma. "Our results strongly indicate that
an arrhythmic clock system, induced by the
absence of CRY proteins, alone is sufficient to
increase the stress level of cells, leading to the
constant expression of inflammatory proteins
and causing low-grade, chronic inflammation."

The researchers demonstrated that a
lack of cryptochrome activates proinflammatory
molecules, indicating a potential role for
cryptochrome in the regulation of inflammatory
cytokine expression. They also found that a
lack of CRY activated the NF-kB pathway, a
molecular signaling conduit that controls many
genes involved in inflammation.

"Every time this pathway is turned on, there
is a residual amount of inflammation left in the
body," says Rajesh Narasimamurthy, a research
associate in Verma's laboratory and the paper's
first author. "That adds up over time, contributing
to inflammation-related conditions like
obesity and diabetes."

The researchers say the goal now is to find
out how to suppress NF-kB activation in the
short term to treat diseases like diabetes. They
caution that any long-term suppression of the
pathway could lead to chronic infection. "We
would like to find molecules that modify this
activity and focus on those small-molecule
inhibitors to treat disease," Verma adds.